Cellular proliferative disorders such as cancer are among the most common causes of death in developed countries. Many cellular proliferative disorders have no available cures or few, if any, treatment options to slow the progression of the disease. For cellular proliferative diseases for which treatments exist, undesirable side effects and limited efficacy often call into question the utility of a given treatment. This is particularly true when the available treatment option(s) may not appreciably prolong life, but have a definitive adverse effect on the quality of time remaining. Thus, identifying new effective drugs for cellular proliferative disorders, and in particular cancer, is a continuing focus of medical research.
Oncogenic activation of the gene RAS via point mutations occurs in more than 30% of all human cancers. RAS-driven human cancers remain the most difficult to treat. Constitutive activation of downstream effector pathways by oncogenic RAS results in the uncontrolled growth, proliferation, and survival of cancer cells. See Gysin et al., Genes Cancer. 2011 March; 2(3): 359-372 for a review of therapeutic strategies for targeting RAS proteins. Aberrant RAS activity as a result of oncogenic mutations causes de novo cell transformation and promotes tumor growth and progression.
RAS interacts with a large number of effector proteins by a highly conserved mechanism that involves the switch region of RAS and the RAS-binding domains (RBDs) of its effector proteins, such as the effector protein RAF. Upon activation by RAS, RAF phosphorylates and activates the serine/threonine kinase MEK, which in turn phosphorylates and activates the serine/threonine kinase ERK. This series of signaling events results in the activation of transcriptional regulators that promote a wide variety of cellular events, including cell cycle progression and cell proliferation. Tight regulation of the RAS activation status is critical for cell physiology. Mutations that convert RAS into an oncoprotein are found in up to 25% of human tumors. Prior et al., Cancer Res 2012, 72(10):2457-2467.
Because RAS' interactions with its effector proteins plays an essential role in oncogenic RAS function, inhibiting those interactions constitutes an attractive therapeutic approach for treatment of cancer.
Rigosertib, a benzylstyryl sulfone, been shown to binds to the RBDs of various RAS effector proteins. See, Divakar, et al., Cancer Res 2014; 74(19 Suppl): Abstract nr LB-108; Reddy et al., Blood, December 2014; 124 (21) 5616. The compound inhibits RAS binding to RAF and other RAS effector proteins such as the PI3K family of proteins as well as RalGDS, thereby blocking the effector protein's interaction with RAS. A consequence of inhibiting RAS binding to RAF appears to be a block in growth factor-induced activation of RAF kinase activity in vivo, and the resulting inability of RAF proteins to form dimers and activate MEK and ERK. A block in the activation of MEK/ERK pathways results.